This invention relates to the identification of a cell cycle control molecule in Pneumocystis carinii.
Pneumocystis carinii (P. carinii) causes severe pneumonia in patients with chronic immunosuppression. Although P. carinii pneumonia is most frequently associated with acquired immune deficiency syndrome (AIDS), patients with solid tumors, hematological malignancies, organ transplantation, and inflammatory conditions requiring prolonged immunosuppression with corticosteroids or cytotoxic agents are also at increased risk for developing P. carinii pneumonia. The mortality of P. carinii pneumonia remains an unacceptable 15% to 40%, being substantially higher in immunosuppressed patients without AIDS. In addition, medications currently used for preventing and treating P. carinii pneumonia are associated with significant side effects in many patients, limiting their use. Therefore, development of newer classes of therapeutic agents for this infection remains a pressing concern.
P. carinii has been shown to be of fungal origin on the basis of riboscmal RNA gene homology and enzyme biochemistry studies. Phylogenetically, P. carinii is most closely related to the fission yeast Schizosaccharomyces pombe, and to the Ustomycetous red yeast fungus. A complete understanding of the life cycle of P. carinii is currently lacking, confounding the ability to culture this organism. Ultrastructural studies indicate that P. carinii has a unique life cycle consisting of both diminutive trophozoites about 1-2 microns in size and larger cystic forms about 8 microns in size. The interaction of trophozoites with alveolar epithelial cells is an integral component of the organism's life cycle and modulates cellular proliferation. Despite numerous efforts employing a variety of cell lines, media, and methodologies, the in vitro cultivation of P. carinii has met with rather limited success and no system yet exists to maintain P. carinii continuously in a cell free system. The limited availability of short term culture and inability to propagate P. carinii has rendered basic studies of this organism difficult, hampering development of new therapies.